Figure 2.

Schematic overview of DNL and its transcriptional regulation. Carbohydrates, including glucose or fructose enter hepatocyte cells and become a sensor for DNL activation. Glucose is converted to G6P followed by isomerization to F6P and F2,6P through the glycolysis process. By contrast, fructose also converts to Gly-3P through fructolysis and further converts to F2,6P. G6P and F2,6P induce dephosphorylation of ChREBP, and it detaches from 14-3-3 protein into an active form. Moreover, the activation of insulin receptor leads to the phosphorylation of IRS1, further activating the mTORC pathway and induces the nuclear translocation of SREBP1c. In the feedback response, SIRT1 and AMPK prevent the nuclear translocation of ChREBP and SREBP1c, resulting in the inhibition of DNL transcriptional regulation. DNL, de novo lipogenesis; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; Gly-3P, glycerol 3-phosphate; F2,6P, fructose 2,6-bisphosphate; ChREBP, carbohydrate response element-binding protein; IRS1, insulin receptor substrate 1; mTORC, mammalian target of rapamycin complex; SREBP1c, sterol regulatory element-binding protein 1c; SIRT1, Sirtuin 1; AMPK, AMP-activated protein kinase.